COMBINED EFFECTS OF PKC ACTIVATION DURING NORADRENERGIC STIMULATION IN NEURAL SYSTEMS

Spinal cord injury (SCI) is a devastating neurological condition that imposes a substantial burden on patients, their families, and healthcare systems. A key pathological feature of SCI is the loss of neuronal function caused by a hostile inflammatory microenvironment within the injured spinal cord.
This study investigates the synergistic effects of the endogenous neurotransmitter noradrenaline (NE) and the protein kinase C (PKC) modulator bryostatin-1 (B1) on neuroinflammation and microglial function. Using fluorescent primary neural cell culture models, we examined the singular and combined impact of NE and B1 on neurite outgrowth, microglial activity, and inflammatory signalling. Co-treatment markedly potentiated the effects of NE on activating microglia, microglial migration, phagocytosis, and oxidative stress. B1 alone modestly enhanced neurite growth. The co-treatment also suppressed pro-inflammatory marker expression. However, depending on the inflammatory conditions, we observed a spatial shift from beta-adrenergic signalling toward a combined beta- and alpha-noradrenergic regulation and therefore an indication of increased involvement of PKC-mediated anti-inflammatory pathways. Notably, the synergistic effects of NE and B1 were more pronounced in activated microglia compared to resting cells. This was demonstrated in an in vitro injury model, where microglia at the lesion site exhibited enhanced phagocytic activity upon NE and B1 co-stimulation, whereas cells in surrounding regions remained unaffected.
In conclusion, our findings suggest that a combinatorial pleiotropic approach using NE and B1 is more effective than mono-therapeutic strategies in promoting neuroimmune modulation and neural restoration. These results provide novel insights into noradrenergic signaling and PKC activation as potential therapeutic targets for SCI.